Monoglyceride/lactate ester permeation enhancer for oxybutynin

ABSTRACT

A composition of matter for application to a body surface or membrane to administer oxybutynin by permeation through the body surface or membrane, the composition comprising, in combination the oxybutynin to be administered, in a therapeutically effective amount; and a permeation enhancing mixture comprising a monoglyceride or a mixture of monoglycerides, and a lactic ester or a mixture of lactate esters, present in specific concentrations.

RELATED APPLICATIONS

This application is a 371 of PCT/US94/11226, filed Sep. 29, 1994, and acontinuation-in-part of U.S. application Ser. No. 08/129,494, filed Sep.29, 1993, now abandoned, which application is incorporated herein, inits entirety by reference, and benefit is claimed of its filing date.

FIELD OF THE INVENTION

This invention relates to the transdermal delivery of biologicallyactive oxybutynin. More particularly, this invention relates to novelmethods and compositions for enhancing the percutaneous absorption ofoxybutynin when incorporated in transdermal drug delivery systems. Moreparticularly, but without limitation thereto, this invention relates tothe transdermal delivery of oxybutynin utilizing a permeation-enhancingmixture of a monoglyceride and a lactate ester. Still more particularly,but without limitation thereto this invention relates to the transdermaldelivery of oxybutynin utilizing a permeation-enhancing mixture of amonoglyceride and a lactate ester, wherein the composition contains from15 to 25 wt % of a monoglyceride or monoglyceride mixture and from 8 to25 wt % of lactate ester.

BACKGROUND OF THE INVENTION

The transdermal route of parenteral delivery of drugs provides manyadvantages over other administrative routes, and transdermal systems fordelivering a wide variety of drugs or other beneficial agents aredescribed in U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731,683; 3,797,494;4,031,894; 4,201,211; 4,286,592; 4,314,557; 4,379,454; 4,435,180;4,559,222; 4,568,343; 4,573,995; 4,588,580; 4,645,502; 4,704,282;4,788,062; 4,816,258; 4,849,226; 4,908,027; 4,943,435; and 5,004,610.The disclosures of the above patents are incorporated herein byreference.

In many instances, drugs which would appear to be ideal candidates fortransdermal delivery are found to have such low permeability throughintact skin that they cannot be delivered at therapeutically effectiverates from reasonably sized systems.

In an effort to increase skin permeability, it has been proposed topretreat the skin with various chemicals or to concurrently deliver thedrug in the presence of a permeation enhancer. Various materials havebeen suggested for this purpose, as described in U.S. Pat. Nos.3,472,931, 3,527,864, 3,896,238, 3,903,256, 3,952,099, 4,046,886,4,130,643, 4,130,667, 4,299,826, 4,335,115, 4,343,798, 4,379,454,4,405,616 and 4,746,515, all of which are incorporated herein byreference; British Pat. No. 1,001,949; and Idson, PercutaneousAbsorption, J. Pharm. Sci., vol. 64, No. b6, June 1975, pp 901-924(particularly 919-921).

To be considered useful, a permeation enhancer should have the abilityto enhance the permeability of the skin for at least one and preferablya significant number of drugs. More importantly, it should be able toenhance the skin permeability such that the drug delivery rate from areasonably sized system (preferably 5-50 cm²) is at therapeutic levels.Additionally, the enhancer, when applied to the skin surface, should benon-toxic, non-irritating on prolonged exposure and under occlusion, andnon-sensitizing on repeated exposure. Preferably, it should be capableof delivering drugs without producing topical reactions, burning ortingling sensations.

The present invention greatly increases oxybutynin permeability throughthe skin, and also reduces the lag time between application of theoxybutynin to the skin and attainment of the desired therapeutic effect.

While it is known in the art to combine permeation enhancers, thisinvention utilizes a novel combination of a monoglyceride and a lactateester. Further, the invention utilizes a specific concentration of eachof the novel components. The combined effect and, further, specificconcentrations of the components produce a significant and surprisingimprovement over use of either a monoglyceride or a lactate ester aloneor the combination in nonspecified concentrations.

Neurogenic bladder disease is a disorder involving loss of control ofurination. The major symptoms of this disease are urinary frequency,urinary retention or incontinence. There are two types of lesions thatcause a neurogenic bladder. The first, upper motoneuron lesion, leads tohypertonia and hyperreflexia of the bladder, a spastic condition, givingrise to symptoms of urinary frequency and incontinence. The secondlesion, a lower motoneuron lesion, involves hypotonia and hyporeflexiaof the bladder. The major symptoms in this condition are urinaryretention, since the voiding reflex has been lost, and incontinence,which occurs when the bladder "leaks", being full to overflowing.

The majority of neurogenic bladder patients have the spastic orhypertonic bladder. The clinician usually attempts to convert thecondition of hyperreflexia and hypertonia to hypotonia, thereby treatingthe primary problem of incontinence. When the condition has beenconverted to hypotonia, it can be managed by intermittentcatheterization. However, there is a significant population of patientswho cannot be converted completely from the hypertonic to the hypotoniccondition, and who still find they have to urinate every hour or areincontinent.

The use of oxybutynin chloride, as approved by the FDA in the UnitedStates, is described in the 1992 Physician's Desk Reference, pages 1332through 1333 with reference to the drug Ditropan® manufactured by MarionMerrell Dow. Oxybutynin is normally administered to human beings orallyat relatively high doses (5 mg tablets taken two to four times a day).Oxybutynin has been incorporated into tablets, capsules, granules orpills containing 1-5 mg, preferably 5 mg, of oxybutynin chloride, syrupscontaining 1-5 mg, preferably 5 mg, of oxybutynin chloride per 5 mL andtransdermal compositions (creams or ointments) containing 1-10 weightpercent ("wt %") oxybutynin chloride. See, BE 902605.

In U.S. Pat. No. 4,747,845, oxybutynin was listed as an agent that couldbe incorporated into a transdermal synthetic resin matrix system forextended duration drug release, but oxybutynin was not used in thedevice. In U.S. Pat. No. 4,928,680 oxybutynin was given as apharmacologically active agent suitable for transdermal delivery, but aswith the above reference, oxybutynin was not incorporated into thedevice.

Oxybutynin has been incorporated into a device having a waterimpermeable barrier layer, a reservoir containing oxybutynin in contactwith the inner surface of the barrier layer and a removable protectorlayer in contact with the other surface of the reservoir. The reservoirwas a polyurethane fiber mat impregnated with an aqueous solutioncontaining 25 mg/mL of oxybutynin. The device was placed on a 20 μmthick polybutadiene film. The non-barrier carrying surface was incontact with 0.05M isotonic phosphate buffer solution. The in vitrorelease rate measured was approximately 12 mg over 24 hours through a 49cm² area or 10 μg/cm² ·hr. (U.S. Pat. No. 4,784,857 and EP 0 250 125).

In Pharm Res, "Development of Transdermal Delivery Systems ofOxybutynin: In-Vivo Bioavailability", P. Keshary et al, (NY)8 (10 Supp)1991, p. S205 three types of transdermal delivery systems, usingmatrix-diffusion controlled and membrane-permeation controlledtechnologies were discussed. The in vitro permeation rate of about 9, 12and 12 μg/cm² ·hr and in vitro release rates (sink condition) of about1160, 402 and 57.2 μg/cm² ·hr were obtained from Silastic monolithic,acrylic pressure sensitive adhesive matrix and reservoir type deliverysystems, respectively. In humans, steady state plasma concentrations ofabout 1.86 ng/mL were obtained after 6 hours of application of a single20 cm² patch of the acrylic pressure sensitive adhesive matrix type.

While it is known in the art to formulate a dual permeation enhancersystem, see eg, European patent publication numbers 0295411 and 0368339,this invention utilizes a novel combination of oxybutynin with amonoglyceride and a lactate ester. Further, the invention utilizes novelconcentrations of the monoglyceride/lactate ester permeation enhancercombination. The combined effect of these two permeation enhancers andfurther, the specific concentrations, ie, 15 to 25 wt % of monoglycerideand 8 to 25 wt % of lactic acid ester, produces a significant andsurprising improvement, ie, more than an additive effect, over use ofeither a monoglyceride or a lactate ester alone with oxybutynin or thecombination in nonspecified concentrations.

SUMMARY OF THE INVENTION

The present invention relates to improved compositions and methods forimproving the penetration of oxybutynin while producing little or noskin irritation. The system of the invention comprises a carrier ormatrix adapted to be placed in oxybutynin and permeation-enhancingmixture-transmitting relation to the selected skin or other body site.The carrier or matrix contains sufficient amounts of oxybutynin and thepermeation-enhancing mixture to continuously coadminister to the site,over a predetermined delivery period, oxybutynin, in a therapeuticallyeffective amount, and the permeation-enhancing mixture of amonoglyceride and a lactate ester which are present in specificconcentrations, ie, 15 to 25 wt % of monoglyceride and 8 to 25 wt % of alactate ester, preferably 20 wt % monoglyceride and 12 wt % lactateester, in an amount effective to enhance the permeation of the drug tothe skin.

As used herein, the term "transdermal" delivery or application refers tothe delivery or application of oxybutynin by passage through skin,mucosa and/or other body surfaces by topical application or byiontophoresis.

As used herein, the term "therapeutically effective" amount or raterefers to the amount or rate of oxybutynin needed to effect the desiredtherapeutic result.

As used herein, the term "monoglyceride" refers to glycerol monooleate,glycerol monolaurate and glycerol monolinoleate, or a mixture thereof.Monoglycerides are generally been available as a mixture ofmonoglycerides, with the mixture deriving its name from themonoglyceride present in the greatest amount. In a preferred embodimentof this invention, the permeation enhancer is glycerol monolaurate.

As used herein, the term "glycerol monooleate" refers to glycerolmonooleate itself or a mixture of glycerides wherein glycerol monooleateis present in the greatest amount.

As used herein, the term "glycerol monolaurate" refers to glycerolmonolaurate itself or a mixture of glycerides wherein glycerolmonolaurate is present in the greatest amount.

As used herein, the term "glycerol monolinoleate" refers to glycerolmonolinoleate itself or a mixture of glycerides wherein glycerolmonolinoleate is present in the greatest amount.

As used herein, the term "lactate ester" or "lactic ester of an alcohol"refers to ethyl lactate, lauryl lactate, myristyl lactate or cetyllactate, or a mixture thereof. Preferably, the lactate ester is lauryllactate or ethyl lactate or a mixture thereof.

As used herein, the term "substantial portion of the time period" meansat least about 60% of the time period, preferably at least about 90% ofthe time period. Correlatively, the term "substantially constant" meansa variation of less than about ±20%, preferably less than about ±10%,over a substantial portion of the time period.

As used herein, the term "permeation enhancing mixture" refers to amixture comprising one or more lactate esters and one or moremonoglycerides. The monoglyceride or monoglyceride mixture, preferablyglycerol monolaurate, is present in specific concentrations. The lacticacid ester, eg, lauryl, myristyl, cetyl, ethyl, methyl or oleic acid,benzoic acid or lactic acid is also present in specific concentrations.The monoglyceride is present in the range of about 15 to about 25 weightpercent and lactate ester is present in the range of about 8 to abut 25weight percent. More preferably, the permeation enhancer mixture byweight comprises 20% GML and 12% lauryl lactate.

As used herein, the term "predetermined delivery period" or "extendedtime period" refers to the delivery of oxybutynin for a time period offrom several hours to seven days or longer. Preferably, the time periodis from 16 hours to 3 or 4 days.

As used herein, the term "permeation enhancing amount or rate" refers tothe rate or amount that provides increased permeability of theapplication site to oxybutynin.

As used herein, the term "poly-N-vinyl amide" means a cross-linkedpoly-N-vinyl amide or combination of poly-N-vinyl amide such aspoly-N-vinylmethylacetamide, poly-N-vinylethylacetamide,poly-N-vinylmethylisobutyramide, poly-N-vinyl-2-pyrrolidone,poly-N-vinylpyrrolidone, poly-N-vinyl-2-piperidone,poly-N-vinyl-caprolactam, poly-N-vinyl-5-methyl-2-pyrrolidone,poly-N-vinyl-3-methyl-2-pyrrolidone, and the like. Preferably, thepoly-N-vinyl amide is poly-N-vinyl-2-pyrrolidone (more preferablyPolyplasdone XL®, Polyplasdone XL-10®, GAF).

The invention will be described in further detail with reference to theaccompanying figures wherein:

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a cross-sectional view of one embodiment of the transdermaldrug delivery system according to this invention;

FIG. 2 is a cross-sectional view of another embodiment of thetransdermal drug delivery system of this invention;

FIG. 3 is a cross-sectional view of still another embodiment of thetransdermal drug delivery system according to this invention;

FIG. 4 is a cross-sectional view of yet another embodiment of thetransdermal drug delivery system of this invention;

FIG. 5 is a graph of the flux of oxybutynin through human epidermis at35° C., in vitro, with glycerol monolaurate and lauryl lactate.

FIG. 6 is a graph of the flux of oxybutynin through human epidermis at35° C., in vitro, with glycerol monolaurate and lauryl lactate.

FIG. 7 is a graph of the flux of oxybutynin through human epidermis at35° C., in vitro, with glycerol monolaurate and lauryl lactate.

FIG. 8 is a graph of the cumulative amount of oxygen through humanepidermis with varying glycerol monolaurate and lauryl lactate.

FIG. 9 is a graph of the cumulative amount of oxygen through humanepidermis with varying glycerol monolaurate and lauryl lactate.

FIG. 10 is a bar graph of the effect of glycerol monolaurate and lauryllactate on the flux of oxybutynin through human epidermis at 35° C., invitro.

FIG. 11 is a graph of the effect of a microporous membrane on the rateof oxybutynin.

FIG. 12 is a graph of the effect of a microporous membrane on the fluxof oxybutynin through human epidermis at 35° C., in vitro.

FIG. 13 is a graph of the effect of a microporous membrane on the fluxof oxybutynin through human epidermis at 35° C., in vitro.

DETAILED DESCRIPTION OF THE INVENTION

This invention codelivers one or more monoglycerides and one or morelactate esters to aid in delivery of oxybutynin across the skin. Inaddition thereto, this invention calls for the monoglycerides andlactate esters to be present in specific concentrations. The combinedeffect and preferred concentrations according to this invention havebeen shown to produce dramatic increases, ie, more than an additiveeffect, in the permeation of oxybutynin when compared to the use ofeither a lactate ester or a monoglyceride alone or the two components innonspecified concentrations. Improved enhancement of oxybutyninpermeation according to this invention, can be obtained over arelatively wide concentration range of lactate ester and monoglycerideweight ratios, however, the inventors have found 20 wt % monoglycerideand 12 wt % lactate ester to provide the greatest enhancement withoutany negative side effects.

The present invention in one embodiment is directed to a composition ofmatter for application to a body surface or membrane to administeroxybutynin by permeation through the body surface or membrane, thecomposition comprising, in combination:

(a) the oxybutynin to be administered, in a therapeutically effectiveamount; and

(b) a permeation-enhancing mixture comprising:

(i) 15 to 25 wt % of a monoglyceride or a mixture of monoglycerides, and

(ii) 8 to 25 wt % of a lactate ester or a mixture of lactate esters.

The oxybutynin may be present in the composition in an amount rangingfrom 0.01 to 50% by weight. The permeation-enhancing mixture preferablycontains the monoglyceride and lactate ester to be present inapproximately 20 wt % and 12 wt %, respectively.

This invention finds particular usefulness in enhancing permeability ofoxybutynin across skin. However, it is also useful in enhancingoxybutynin flux across mucosa. Further, this invention is useful indelivery of oxybutynin both systemically and topically. According to ourinvention, the permeation-enhancing mixture and oxybutynin to bedelivered are placed in drug- and permeation-enhancingmixture-transmitting relationship to the appropriate body surface,preferably in a pharmaceutically acceptable carrier therefor, andmaintained in place for the desired period of time.

The oxybutynin and the permeation-enhancing mixture are typicallydispersed within a physiologically compatible matrix or carrier as morefully described below which may be applied directly to the body as anointment, gel, cream, suppository or sublingual or buccal tablet, forexample. When used in the form of a liquid, ointment, lotion, cream orgel applied directly to the skin, it is preferable, although notrequired, to occlude the site of administration. Such compositions canalso contain other permeation enhancers, stabilizers, dyes, diluents,pigments, vehicles, inert fillers, excipients, gelling agents,vasoconstrictors, and other components of topical compositions as areknown to the art.

In other embodiments, the oxybutynin and permeation enhancing mixturewould be administered from a transdermal delivery device as more fullydescribed below. Examples of suitable transdermal delivery devices areillustrated in FIGS. 1, 2, 3 and 4. In the drawings, the same referencenumbers are used throughout the different figures to designate the sameor similar components. The figures are not drawn to scale.

In FIG. 1, transdermal delivery device 10 comprises a reservoir 12containing the oxybutynin and the permeation-enhancing mixture.Reservoir 12 is preferably in the form of a matrix containing theoxybutynin and permeation enhancing mixture dispersed therein. Reservoir12 is sandwiched between a backing layer 14 and an in-line contactadhesive layer 16. The device 10 adheres to the surface of the skin 18by means of the adhesive layer 16. The adhesive layer 16 may optionallycontain the permeation enhancing mixture and/or oxybutynin. A strippablerelease liner (not shown in FIG. 1) is normally provided along theexposed surface of adhesive layer 16 and is removed prior to applicationof device 10 to the skin 18. Optionally, a rate-controlling membrane(not shown) may be present between the reservoir 12 and the adhesivelayer 16. In addition, a microporous membrane (not shown) is preferablyplaced on the skin-distal side of the adhesive layer.

Alternatively, as shown in FIG. 2, transdermal therapeutic device 20 maybe attached to the skin or mucosa of a patient by means of an adhesiveoverlay 22. Device 20 is comprised of a drug- and permeation enhancingmixture-containing reservoir 12 which is preferably in the form of amatrix containing the drug and the enhancing mixture dispersed therein.A backing layer 14 is provided adjacent one surface of reservoir 12.Adhesive overlay 22 maintains the device on the skin and may befabricated together with, or provided separately from, the remainingelements of the device. With certain formulations, the adhesive overlay22 may be preferable to the in-line contact adhesive 16 as shown inFIG. 1. Backing layer 14 is preferably slightly larger than reservoir12, and in this manner prevents the materials in reservoir 12 fromadversely interacting with the adhesive in overlay 22. Optionally, arate-controlling membrane (not shown in FIG. 2) may be provided on theskin-proximal side of reservoir 12. A strippable release liner 24 isalso provided with device 20 and is removed just prior to application ofdevice 20 to the skin.

In FIG. 3, transdermal delivery device 30 comprises a drug- andpermeation enhancing mixture-containing reservoir ("drug reservoir") 12substantially as described with respect to FIG. 1. Permeation enhancerreservoir ("enhancer reservoir") 26 comprises the permeation enhancingmixture dispersed throughout and contains the drug at or belowsaturation. Enhancer reservoir 26 is preferably made from substantiallythe same matrix as is used to form drug reservoir 12. A rate-controllingmembrane 28 for controlling the release rate of the permeation enhancerfrom enhancer reservoir 26 to drug reservoir 12 is placed between thetwo reservoirs. A rate-controlling membrane (not shown in FIG. 3) forcontrolling the release rate of the enhancer from drug reservoir 12 tothe skin may also optionally be utilized and would be present betweenadhesive layer 16 and reservoir 12. In addition, a microporous membrane(not shown) may be present on the skin-distal side of adhesive layer 16.

The rate-controlling membrane may be fabricated from permeable,semipermeable or microporous materials which are known in the art tocontrol the rate of agents into and out of delivery devices and having apermeability to the permeation enhancer lower than that of drugreservoir 12. Suitable materials include, but are not limited to,polyethylene, polyvinyl acetate, ethylene n-butyl acetate and ethylenevinyl acetate copolymers.

The microporous membrane is employed as a tie layer between the drugreservoir and contact adhesive. The purpose of the layer is to reinforcethe adhesion and prevent blooming and delamination of the contactadhesive from the drug reservoir layer. Blooming and delaminating arecommon problems when amphipathic molecules such as non-ionicsurfactants, eg, monoglycerides, are utilized in the transdermaldelivery devices.

A microporous tie layer should interconnect the drug reservoir andcontact adhesive but should not affect the flux or release rateprofiles. The layers should also have a low or negligible solubility ofthe surfactant or drug. The layers useful in this invention include, butare not limited to, microporous polypropylene, microporous polyethylene,porous polycarbonate and spunbonded filamentous material.

Superimposed over the permeation enhancer reservoir 26 of device 30 is abacking 14. On the skin-proximal side of reservoir 12 are an adhesivelayer 16 and a strippable liner 24 which would be removed prior toapplication of the device 30 to the skin.

In the embodiments of FIGS. 1, 2 and 3, the carrier or matrix materialof the reservoirs has sufficient viscosity to maintain its shape withoutoozing or flowing. If, however, the matrix or carrier is a low-viscosityflowable material such as a liquid or a gel, the composition can befully enclosed in a pouch or pocket, as known to the art from U.S. Pat.No. 4,379,454 (noted above), for example, and as illustrated in FIG. 4.Device 40 shown in FIG. 4 comprises a backing member 14 which serves asa protective cover for the device, imparts structural support, andsubstantially keeps components in device 40 from escaping the device.Device 40 also includes reservoir 12 which contains the oxybutynin andpermeation enhancing mixture and bears on its surface distant frombacking member 14 a rate-controlling membrane 28 for controlling therelease of oxybutynin and/or permeation enhancing mixture from device40. The outer edges of backing member 14 overlay the edges of reservoir12 and are joined along the perimeter with the outer edges of therate-controlling membrane 28 in a fluid-tight arrangement. This sealedreservoir may be effected by pressure, fusion, adhesion, an adhesiveapplied to the edges, or other methods known in the art. In this manner,reservoir 12 is contained wholly between backing member 14 andrate-controlling membrane 28. On the skin-proximal side ofrate-controlling membrane 28 are an adhesive layer 16 and a strippableliner 24 which would be removed prior to application of the device 40 tothe skin.

In an alternative embodiment of device 40 of FIG. 4, reservoir 12contains the permeation enhancing mixture and the oxybutynin at or belowsaturation. Oxybutynin at or above saturation and an additional amountof permeation enhancing mixture are present in adhesive layer 16 whichacts as a separate reservoir.

The oxybutynin and permeation enhancing mixture can be co-extensivelyadministered to human skin or mucosa by direct application to the skinor mucosa in the form of an ointment, gel, cream or lotion, for example,but are preferably administered from a skin patch or other knowntransdermal delivery device which contains a saturated or unsaturatedformulation of the drug and the enhancer. The formulation is non-aqueousbased and is designed to deliver the oxybutynin and the permeationenhancing mixture at the necessary fluxes. Typical non-aqueous gels arecomprised of silicone fluid or mineral oil. Mineral oil-based gels alsotypically contain 1-2 wt % of a gelling agent such as colloidal silicondioxide. The suitability of a particular gel depends upon thecompatibility of its constituents with both oxybutynin and thepermeation enhancing mixture and any other components in theformulation.

The reservoir matrix should be compatible with oxybutynin, thepermeation enhancer and any carrier therefor. The term "matrix" as usedherein refers to a well-mixed composite of ingredients fixed into shape.

When using a non-aqueous-based formulation, the reservoir matrix ispreferably composed of a hydrophobic polymer. Suitable polymericmatrices are well known in the transdermal drug delivery art, andexamples are listed in the above-named patents previously incorporatedherein by reference. A typical laminated system would comprise apolymeric membrane and/or matrix such as ethylene vinyl acetate (EVA)copolymers, such as those described in U.S. Pat. No. 4,144,317,preferably having a vinyl acetate (VA) content in the range of fromabout 9% up to about 60% and more preferably about 9% to 40% VA.Polyisobutylene/oil polymers containing from 4-25% high molecular weightpolyisobutylene and 20-81% low molecular weight polyisobutylene with thebalance being an oil such as mineral oil or polyisobutynes may also beused as the matrix material.

The amount of oxybutynin present in the therapeutic device and requiredto achieve an effective therapeutic result depends on many factors, suchas the minimum necessary dosage of the oxybutynin for the particularindication being treated; the solubility and permeability of the matrix,of the adhesive layer and of the rate-controlling membrane, if present;and the period of time for which the device will be fixed to the skin.The minimum amount of oxybutynin is determined by the requirement thatsufficient quantities of oxybutynin must be present in the device tomaintain the desired rate of release over the given period ofapplication. The maximum amount for safety purposes is determined by therequirement that the quantity of oxybutynin present cannot exceed a rateof release that reaches toxic levels.

The oxybutynin present in the device may be either the racemateS-oxybutynin, or R-oxybutynin. Surprisingly, the inventors discoveredthat the flux of R- or S-oxybutynin is approximately equivalent to thatof the racemate. This discovery allows for the use of a patch, when eg,only R-oxybutynin is delivered, that is at least one-half the size ofthe patch required to deliver the equivalent amount of the racemate.

The oxybutynin is normally present in the matrix or carrier at aconcentration in excess of saturation, the amount of excess being afunction of the desired length of the drug delivery period of thesystem. The oxybutynin may, however, be present at a level belowsaturation without departing from this invention as long as the drug iscontinuously administered to the skin or mucosal site in an amount andfor a period of time sufficient to provide the desired therapeutic.

The permeation enhancing mixture is dispersed through the matrix orcarrier, preferably at a concentration sufficient to providepermeation-enhancing amounts of enhancer in the reservoir throughout theanticipated administration period. Where there is an additional,separate permeation enhancer matrix layer as well, as in FIGS. 3 and 4,the permeation enhancer normally is present in the separate reservoir inexcess of saturation.

The unexpected effects of the specific weight percentages of thecomponents of the permeation enhancer mixture are believed to be due, inpart, to the solubility of the monoglyceride in the lactic acid ester.It is known that monoglycerides by themselves are effective permeationenhancers. The enhancement occurs by the solubilization of themonoglyceride in the lipid layer of the skin. The solubilization of themonoglyceride in the lipid layer increases as a function of lactic acidester concentration. For example, the solubility of glycerol monolauratein lauryl lactate is 350 mg/g of solution when the solution is stirred.GML is practically insoluble in, for example an EVA 40 matrix. Thus, theamount of GML dissolved, ie, free GML, is dictated by and proportionalto the lauryl lactate loading in the polymer.

Based on the GML solubility of 350 mg/g, free GML concentrations basedupon varying weight percents of lauryl lactate in EVA 40 are as follows:

    ______________________________________                                        Wt % lauryl lactate                                                                          Wt % GML in solution                                           ______________________________________                                        12%            4.2%                                                           20%            7.0%                                                           27%            9.5%                                                           30%            10.5%                                                          ______________________________________                                    

Thus, based upon the amount of GML in solution it would have appearedthat the higher wt % of lauryl lactate would have resulted in a higherlevel of free GML and thus greater efficacy in increasing permeation.However, as shown by the examples, the preferred formulations,containing 20 wt % GML and 12 wt % lauryl lactate were equally effectivein enhancing drug permeability as those containing 20 wt % GML and 20 wt% lauryl lactate. While the invention is directed to a permeationenhancing mixture containing a monoglyceride or monoglyceride mixturefrom 15 to 25 wt % and a lactic acid ester present from 8 to 25 wt %,the 20 wt % monoglyceride and 12 wt % lactic acid ester is preferredbecause it is as effective as the higher percentage lactic acid estercompositions, yet it delivers less of a lactic acid ester, a knownpotential irritant.

In addition to the oxybutynin and the permeation enhancing mixture,which are essential to the invention, the matrix or carrier may alsocontain dyes, pigments, inert fillers, excipients and other conventionalcomponents of pharmaceutical products or transdermal devices known tothe art.

Because of the wide variation in skin permeability from individual toindividual and from site to site on the same body, it may be preferablethat the oxybutynin and permeation enhancing mixture be administeredfrom a rate-controlled transdermal delivery device. Rate control can beobtained either through a rate-controlling membrane or adhesive or bothas well as through the other means.

A certain amount of oxybutynin will bind reversibly to the skin, and itis accordingly preferred that the skin-contacting layer of the deviceinclude this amount of oxybutynin as a loading dose.

The surface area of the device of this invention can vary from less than1 cm² to greater than 200 cm². A typical device, however, will have asurface area within the range of about 5-50 cm².

The devices of this invention can be designed to effectively deliveroxybutynin for an extended time period of from several hours up to 7days or longer. Seven days is generally the maximum time limit forapplication of a single device because the adverse affect of occlusionof a skin site increases with time and the normal cycle of sloughing andreplacement of the skin cells occurs in about 7 days.

The method of this invention comprises:

(a) administering oxybutynin, in a therapeutically effective amount, tothe area of skin over the time period; and

(b) coadministering the permeation-enhancing mixture according to thisinvention to the area of skin.

Preferably, the composition delivered by this method contains asufficient amount of permeation enhancing mixture, ie, 15 to 25 wt % ofa monoglyceride or monoglyceride mixture and 8 to 25 wt % of a lactateester and enough oxybutynin, in combination, to provide systemicadministration of oxybutynin through the skin for a predetermined periodof time for the oxybutynin to provide an effective therapeutic result.

The invention is also directed to a method for the transdermaladministration of a therapeutically effective amount of oxybutynintogether with a skin permeation-enhancing amount of a lactate ester anda monoglyceride or monoglyceride mixture preferably present in about 8to 25 wt % and 15 to 25 wt %, respectively.

According to the present invention, it has been found that oxybutyninmay be administered to the human body in a therapeutically effectiveamount via the transdermal route when it is coadministered with thepermeation enhancing mixture. Representative skin permeation rates ofoxybutynin through living human skin are in the range of about 5 μg/cm²·hr to about 15 μg/cm² ·hr. Therapeutic blood levels can be achievedwithin approximately 6-10 hours after the initial application, and bloodconcentrations are maintained with subsequent system applications. Therange of desired and achievable system permeation rates of oxybutynin,arriving through the skin from a limited area, is 1-20 mg over a periodof 24 hours. The system application is easily adapted for shorter orlonger duration treatments, but generally 72 hours is the duration for asingle application.

A preferred embodiment of the present invention comprises a method oftreating neurogenic bladder disorders, eg, urinary frequency orincontinence. To be useful in treating a neurogenic bladder disorder,oxybutynin should be present in plasma at levels above about 0.5 ng/mL,preferably at levels above about 1 ng/mL and most preferably at levelsof about 2-4 ng/mL. To achieve this result, oxybutynin is delivered at atherapeutic rate of at least about 40-200 μg per hour, but typically ofat least 80 μg/hr, and more typically at about 80-160 μg/hr, for thetreatment period, usually about 24 hours to 7 days.

The length of time of oxybutynin presence and the total amount ofoxybutynin in the plasma can be changed following the teachings of thisinvention to provide different treatment regimens. Thus, they can becontrolled by the amount of time during which exogenous oxybutynin isdelivered transdermally to an individual or animal.

Preferably, a device for the transdermal administration of oxybutynin,at a therapeutically effective rate, comprises:

(a) a reservoir comprising:

(i) 5 to 40% by weight oxybutynin,

(ii) 15 to 25% by weight monoglyceride or mixture of monoglycerides,

(iii) 8 to 25% by weight lactic acid ester, and

(iv) 10 to 72% by weight ethylene vinyl acetate copolymer;

(b) a backing on the skin-distal surface of the reservoir; and

(c) means for maintaining the reservoir in drug- and permeationenhancing mixture-transmitting relation with the skin.

In one embodiment, the device further comprises a microporous membraneon the skin-distal surface of the means for maintaining the reservoir inplace. Preferably, the monoglyceride is glycerol monolaurate and thelactic acid ester is lauryl lactate. In another preferred embodiment,the oxybutynin is R-oxybutynin.

More preferably, a device for the transdermal administration ofoxybutynin, at a therapeutically effective rate, comprises:

(a) a reservoir comprising:

(i) 15 to 30% by weight oxybutynin,

(ii) 15 to 25% by weight glycerol monolaurate,

(iii) 8 to 25% by weight lauryl lactate, and

(iv) 20 to 62% by weight ethylene vinyl acetate copolymer;

(b) a backing on the skin-distal surface of the reservoir; and

(c) means for maintaining the reservoir in drug- and permeationenhancing mixture-transmitting relation with the skin.

Preferably, the device further comprises a microporous membrane on theskin-distal surface of the means for maintaining the reservoir in place.In another preferred embodiment, the oxybutynin is R-oxybutynin.

Still more preferably, a device for the transdermal administration ofoxybutynin, at a therapeutically effective rate, comprises:

(a) a reservoir comprising:

(i) 20 to 25% by weight oxybutynin,

(ii) 20% by weight glycerol monolaurate,

(iii) 12% by weight lauryl lactate, and

(iv) 43 to 48% by weight ethylene vinyl acetate copolymer;

(b) a backing on the skin-distal surface of the reservoir; and

(c) means for maintaining the reservoir in drug- and permeationenhancing mixture-transmitting relation with the skin.

Preferably, the device further comprises a microporous membrane on theskin-distal surface of the means for maintaining the reservoir in place.In another preferred embodiment, the oxybutynin is R-oxybutynin.

In another embodiment, the reservoir further comprises 5-25% mostpreferably, about 20% by weight cross-linked poly-N-vinyl-2-pyrrolidone,eg, N-vinyl-2-pyrrolidone Polyplasdone XL-10®, GAF). Preferably, thebacking is a breathable backing, such as NRU-100-C® (Flexcon, Spencer,Mass.). If an occluded backing is used, preferably it is Medpar® (3M,St. Paul, Minn.). Preferably, the means for maintaining the reservoir indrug and permeation enhancing mixture transmitting relation with theskin is an acrylic contact adhesive, such as MSP041991P, 3M. Preferably,the ethylene vinyl acetate copolymer has a acetate content of 33% or40%.

The aforementioned patents describe a wide variety of materials whichcan be used for fabricating the various layers or components of thetransdermal drug delivery devices according to this invention. Thisinvention therefore contemplates the use of materials other than thosespecifically disclosed herein, including those which may hereafterbecome known to the art to be capable of performing the necessaryfunctions. The following examples are offered to illustrate the practiceof the present invention and are not intended to limit the invention inany manner.

EXAMPLE 1

The drug/permeation enhancer reservoir was prepared by mixing ethylenevinyl acetate copolymer having a vinyl acetate content of 40 percent("EVA 40", U.S.I. Chemicals, Illinois) in an internal mixer (Bra Bendertype mixer) until the EVA 40 pellets fused. Oxybutynin, glycerolmonolaurate and lauryl lactate were then added. The mixture was blended,cooled and calendered to a 6 mil thick film. The compositions of thereservoirs are given in Table

                  TABLE 1                                                         ______________________________________                                        Drug/Permeation Enhancer Reservoir Composition                                (weight percent)                                                              ______________________________________                                        FIG. 5                                                                        ______________________________________                                        oxybutynin/glycerol monolaurate/EVA 40                                        (25/15/60)                                                                    oxybutynin/glycerol monolaurate/lauryl lactate/EVA 40                         (25/15/5/55)                                                                  oxybutynin/glycerol monolaurate/lauryl lactate/EVA 40                         (25/15/10/50)                                                                 oxybutynin/glycerol monolaurate/lauryl lactate/EVA 40                         (25/15/15/45)                                                                 ______________________________________                                        FIG. 6                                                                        ______________________________________                                        oxybutynin/glycerol monolaurate/EVA 40                                        (25/20/55)                                                                    oxybutynin/glycerol monolaurate/lauryl lactate/EVA 40                         (25/20/5/50)                                                                  oxybutynin/glycerol monolaurate/lauryl lactate/EVA 40                         (25/20/10/45)                                                                 oxybutynin/glycerol monolaurate/lauryl lactate/EVA 40                         (25/20/15/40)                                                                 ______________________________________                                        FIG. 7                                                                        ______________________________________                                        oxybutynin/glycerol monolaurate/EVA 40                                        (25/25/50)                                                                    oxybutynin/glycerol monolaurate/lauryl lactate/EVA 40                         (25/25/5/45)                                                                  oxybutynin/glycerol monolaurate/lauryl lactate/EVA 40                         (25/25/10/40)                                                                 oxybutynin/glycerol monolaurate/lauryl lactate/EVA 40                         (25/25/15/35)                                                                 ______________________________________                                    

This film was then laminated to an acrylic contact adhesive (MSP041991P,3M) on one side and Medpar® backing (3M) on the opposite side. Thelaminate was then cut into 2.54 cm² circles using a stainless steelpunch.

Circular pieces of human-epidermis were mounted on horizontal permeationcells with the stratum corneum facing the donor compartment of the cell.The release liner of the system was then removed and the system wascentered over the stratum corneum side of the epidermis. A known volumeof the receptor solution (0.05M sodium phosphate buffer at pH 6) thathad been equilibrated at 35° C. was placed in the receptor compartment.Air bubbles were removed; the cell was capped and placed in a waterbath-shaker at 35° C.

At given time intervals, the entire receptor solution was removed fromthe cells and replaced with an equal volume of fresh receptor solutionspreviously equilibrated at 35° C. The receptor solutions were stored incapped vials at 4° C. until assayed for oxybutynin content by HPLC.

From the drug concentration and the volume of the receptor solutions,the area of permeation and the time interval, the flux of the drugthrough the epidermis was calculated as follows: (drugconcentration×volume of receptor/(area×time)=flux (μg/cm² ·hr).

The fluxes achieved for the different systems are shown in FIGS. 5, 6and 7. The fluxes for the devices that contained glycerol monolaurateand lauryl lactate were higher on average than the fluxes obtained fromthe devices that contained only glycerol monolaurate.

FIGS. 8 and 9 are 3-dimensional depictions of the data displayed inFIGS. 5-7, ie, the varying amounts of GML, lauryl lactate and thecumulative flux of oxybutynin. As depicted by the Figs., 20% by weightGML and 12% by weight lauryl lactate provides the greatest fluxenhancement.

EXAMPLE 2

The drug/permeation enhancer reservoir was prepared by mixing ethylenevinyl acetate copolymer having a vinyl acetate content of 40 percent("EVA 40", U.S.I. Chemicals, Illinois) in an internal mixer (Bra Bendertype mixer) until the EVA 40 pellets fused. Oxybutynin, glycerolmonolaurate and lauryl lactate were then added. The mixture was blended,and calendered to a 5.0 mil thick film. The compositions of thereservoir is given in Table

                  TABLE 2                                                         ______________________________________                                        Drug/Permeation Enhancer Reservoir Composition                                (weight percent)                                                                        Glycerol       Lauryl                                               Oxybutynin                                                                              Monolaurate    Lactate EVA-40                                       ______________________________________                                        25        15             0       60                                           25        15             5       55                                           25        15             10      50                                           25        15             15      45                                           25        20             0       55                                           25        20             5       50                                           25        20             10      45                                           25        20             15      40                                           ______________________________________                                    

This film was then laminated to an acrylic contact adhesive (MSP041991P,3M) on one side and a Medpar® or NRU-100-C® backing (Flexco Co.) on theopposite side. The film was then cut into circles and taped to preventrelease of drug from the system edge.

For each device tested, the adhesive was placed against the stratumcorneum side of a disc of human epidermis that had been blotted dry justprior to use. The excess epidermis was wrapped around the device so thatnone of the device edge was exposed to the receptor solution. The devicecovered with epidermis was attached to the flat side of the Teflonholder of a release rod using nylon netting and nickel wire. The rodswere reciprocated in a fixed volume of receptor solution (0.05M sodiumphosphate buffer at pH 6). The entire receptor solution was changed ateach sampling time. The temperature of the receptor solution in thewater bath was maintained at 35° C.

The receptor solutions were stored in capped vials at 4° C. untilassayed for oxybutynin content by HPLC. The fluxes achieved for thedifferent systems were calculated and are shown in FIG. 10.

EXAMPLE 3

The drug/permeation enhancer reservoir was prepared by mixing ethylenevinyl acetate copolymer having a vinyl acetate content of 40 percent("EVA 40", U.S.I. Chemicals, Illinois) in an internal mixer (Bra Bendertype mixer) until the EVA 40 pellets fused. Oxybutynin, glycerolmonolaurate and lauryl lactate were then added. The mixture was blended,and calendered to a 5 mil thick film. The compositions of the reservoirare given in Table

                  TABLE 3                                                         ______________________________________                                        Drug/Permeation Enhancer Reservoir Composition                                (weight percent)                                                                        Glycerol       Lauryl                                               Oxybutynin                                                                              Monolaurate    Lactate EVA-40                                       ______________________________________                                        25        20             12      43                                           ______________________________________                                    

This film was then laminated to an acrylic contact adhesive (MSP04199P,3M) on one side and spun-lace polyester backing, Sontara NRU-100-C®backing (Flexco Co.) on the opposite side. One-half of the samples alsoincluded a microporous polypropylene membrane (Celgard®, HoechstCelanese) laminated to the skin-distal side of the contact adhesive. Thefilm was then cut into circles and taped to prevent edge release.

For each device tested, the adhesive was placed against the stratumcorneum side of a disc of human epidermis that had been blotted dry justprior to use. The excess epidermis was wrapped around the device so thatnone of the device edge was exposed to the receptor solution. The devicecovered with epidermis was attached to the flat side of the Teflonholder of a release rod using nylon netting and nickel wire. The rodswere reciprocated in a fixed volume of receptor solution (0.05M sodiumphosphate buffer at pH 6). The entire receptor solution was changed ateach sampling time. The temperature of the receptor solution in thewater bath was maintained at 35° C.

The receptor solutions were stored in capped vials at 4° C. untilassayed for oxybutynin content by HPLC. The effect of the Celgard® onthe fluxes and release rates achieved for the different systems is shownin FIGS. 11-13.

EXAMPLES 4-5

The drug/permeation enhancer reservoir was prepared by mixing, dependingon the formulation, either ethylene vinyl acetate copolymer having avinyl acetate content of 40 percent ("EVA 40", U.S.I. Chemicals,Illinois) or mineral oil and petrolatum in an internal mixer (Bra Bendertype mixer) until the EVA 40 pellets fused. Oxybutynin, glycerolmonolaurate and lauryl lactate were then added.

When EVA 40 was used the mixture was blended, cooled and calendered to a5 mil thick film. This film was then laminated to an acrylic contactadhesive (MSP041991P, 3M) on one side and Medpar® backing (3M) on theopposite side. The laminate was then cut into 2.54 cm² circles using astainless steel punch. Circular pieces of human-epidermis were mountedon horizontal permeation cells with the stratum corneum facing the donorcompartment of the cell. The release liner of the system was thenremoved and the system was centered over the stratum corneum side of theepidermis. A known volume of the receptor solution (0.05M sodiumphosphate buffer at pH 6) that had been equilibrated at 35° C. wasplaced in the receptor compartment. Air bubbles were removed; the cellwas capped and placed in a water bath-shaker at 35° C.

When the mineral oil/petrolatum was used, the mixture, containing thedrug and permeation enhancers, was blended/mixed and then poured intothe donor side of a two-side diffusion cell. Pieces of human epidermiswere mounted between the two sides of the diffusion cell. A known volumeof the receptor solution (0.05M sodium phosphate buffer at pH 6) thathad been equilibrated at 35° C. was placed in the receptor compartment.Air bubbles were removed; the cell was capped and placed in a waterbath-shaker at 35° C.

At given time intervals, the entire receptor solution for either systemwas removed from the cells and replaced with an equal volume of freshreceptor solutions previously equilibrated at 35° C. The receptorsolutions were stored in capped vials at 4° C. until assayed foroxybutynin content by HPLC.

The permeation rates achieved for the different systems are shown inTable 4, along with the drug reservoir composition. The fluxes for thedevices/gels that contained only one enantiomer were approximatelyequivalent to those obtained from devices/gels containing the racematemixture.

                  TABLE 4                                                         ______________________________________                                                              Oxybutynin Permeation                                   Drug/Permeation Enhancer Reservoir                                                                  Rate at Study State (μg/h                            Composition           · cm.sup.2)                                    ______________________________________                                        Mineral Oil/Petrolatum/GML/LL/R-oxybutynin                                                          12                                                      32/11/20/12/25                                                                Mineral Oil/Petrolatum/GML/LL/S-oxybutynin                                                          13                                                      32/11/20/12/25                                                                Mineral Oil/Petrolatum/GML/LL/oxybutynin                                                            11                                                      (racemate)                                                                    21/11/20/12/25                                                                EVA-40/GML/LL/oxybutynin (racemate)                                                                 6                                                       43/20/12/25                                                                   EVA-40/GML/LL/R-oxybutynin                                                                          4                                                       43/20/12/25                                                                   EVA-40/GML/LL/S-oxybutynin                                                                          4                                                       43/20/12/25                                                                   ______________________________________                                    

This invention has been described in detail with particular reference tocertain preferred embodiments thereof, but it will be understood thatvariations and modifications can be effected within the spirit and scopeof the invention.

What is claimed is:
 1. A composition of matter for application to a bodysurface or membrane to administer oxybutynin by permeation through thebody surface or membrane, the composition comprising, in combination:(a)oxybutynin to be administered, in a therapeutically effective amount;and (b) a permeation-enhancing mixture comprising:(i) 20 wt % of amonoglyceride or a mixture of monoglycerides, and (ii) 12 wt % of alactate ester or a mixture of lactate esters.
 2. A composition accordingto claim 1 wherein the lactate ester is selected from the groupconsisting of lauryl lactate, ethyl lactate, myristyl lactate, or cetyllactate.
 3. A composition according to claim 1 wherein the mixture oflactate esters is ethyl lactate and lauryl lactate.
 4. A compositionaccording to claims 2 or 3 wherein the monoglyceride is glycerolmonolaurate.
 5. A device for the transdermal administration ofoxybutynin at a therapeutically effective rate, which devicecomprises:(a) an oxybutynin reservoir comprising a therapeuticallyeffective amount of oxybutynin and a skin permeation-enhancing amount ofa permeation mixture comprising:(i) 20 wt % of a monoglyceride or amixture of monoglycerides, and (ii) 12 wt % of a lactate ester or amixture of lactate esters; (b) a backing on the skin-distal surface ofthe reservoir; and (c) means for maintaining the oxybutynin reservoir indrug and permeation enhancing mixture-transmitting relation with theskin.
 6. A device according to claim 5 further comprising a secondreservoir positioned between the backing and the oxybutynin reservoir,the second reservoir comprising an excess of the permeation enhancingmixture and oxybutynin at or below saturation; and a rate-controllingmembrane between the oxybutynin reservoir and the second reservoir.
 7. Adevice according to claims 5 or 6 further comprising a microporousmembrane on the skin-distal side of the maintaining means.
 8. A deviceaccording to claims 5 or 6 wherein the monoglyceride or mixture ofmonoglycerides comprises 20 wt % and the lactate ester comprises 12 wt%.
 9. A device according to claims 5 or 6 wherein the monoglyceride isglycerol monolaurate.
 10. A device according to claims 5 or 6 whereinthe lactate ester is selected from the group consisting of lauryllactate, ethyl lactate, cetyl lactate or myristyl lactate.
 11. A deviceaccording to claims 5 or 6 wherein the mixture of lactate esters isethyl lactate and lauryl lactate.
 12. A device according to claims 5 or6 wherein the monoglyceride is glycerol monolaurate and the lactateester is ethyl lactate or lauryl lactate or a mixture thereof.
 13. Adevice according to claims 5 or 6 wherein the drug is R-oxybutynin. 14.A device according to claim 6 wherein the oxybutynin reservoir also isan adhesive layer which functions as the means for maintaining thereservoirs in relation with the skin.
 15. A device according to claim 10wherein the monoglyceride is glycerol monolaurate.
 16. A deviceaccording to claim 5 or 6 wherein the oxybutynin reservoir comprising20-62% by weight ethylene vinyl acetate copolymer.
 17. A method for thetransdermal administration of oxybutynin which method comprises:(a)administering oxybutynin at a therapeutically effective rate to an areaof skin; and (b) simultaneously administering a permeation enhancingmixture comprising:(i) 20 wt % of a monoglyceride or a mixture ofmonoglycerides, and (ii) 12 wt % of a lactate ester or a mixture oflactate esters; to the area of skin at a rate which is sufficient tosubstantially increase the permeability of the area to the drug.